1. Field of the invention
The present invention relates to an FGF inhibitor, angiogenesis inhibitor and antitumor agent containing complestatin or its derivative as an effective ingredient.
2. Prior Art
Although angiogenesis is a biological phenomenon essential for prefetal formation of the vascular system and organ morphogenesis as well as growth and development of the vascular system accompanying body growth, following the onset of puberty, angiogenesis is not observed in mature individuals with the exception of transient angiogenesis accompanying estrus and pregnancy in women.
On the other hand, pathological increases in vascularization are related to the onset and progress of numerous diseases, including various types of inflammatory diseases (rheumatism, psoriasis), diabetic retinopathy and cancer. The proliferation and metastasis of solid tumors in particular are believed to be intimately involved with angiogenesis.
The first step of angiogenesis is thought to begin with binding by various cell growth factors and so forth to receptors on the surface of vascular endothelial cells resulting in promotion of proliferation and migration of vascular endothelial cells. Fibroblast growth factor (FGF) has been shown to function as a angiogenesis factor in both in vivo and in vitro model experimental systems, and is considered to be one of the angiogenesis factors in pathological states.
On the other hand, binding of cell growth factor to receptors on the surface of cancer cells is considered to be necessary for spontaneous cell proliferation and tumor formation. For example, FGF is known to be produced excessively in many gliomas, and FGF receptors are known to appear. Thus, it is believed that an autocrine mechanism in which FGF produced by the tumor itself stimulates the same tumor functions in the formation of gliomas and other tumors.
Although extremely small amounts of basic fibroblast growth factor (bFGF), a type of FGF, appear at normal sites of the brain, abnormal expression of bFGF is observed in nearly all brain tumors, and receptors for bFGF are present on brain tumor cells. Moreover, it is known in animal experiments that progression of brain tumors is inhibited by an antibody against bFGF. Based on these findings, tumor cells in brain tumors are thought to proliferate by an autocrine mechanism. In cases other than brain tumors as well, blood bFGF levels are known to be remarkably increased in patients with lung cancer, kidney cancer and so forth, and bFGF is believed to be functioning as an autocrine signal of tumor proliferation (see Shoichi Hatanaka, Molecular Medicine, 30, 1057, 1993).
Based on the above, FGF inhibitors are expected to serve as angiogenesis inhibitors and antitumor agents for the prevention, treatment and amelioration of various diseases, as well as research reagents and so forth. Several reports have been published relating to FGF inhibitory substances in the past, but effective substances able to withstand practical use have not yet to be found.
An object of the present invention is to provide an FGF inhibitor, angiogenesis inhibitor and antitumor agent that are useful as pharmaceuticals, etc.
In consideration of the above-mentioned present circumstances, the inventors of the present invention searched for an FGF inhibitory substance having more potent inhibitory activity using a microbial culture broth as the raw material. As a result, they found that microorganisms belonging to the genus Streptomyces produced an FGF inhibitory substance, that said FGF inhibitory substance is complestatin, and that complestatin is useful as an FGF inhibitor, angiogenesis inhibitor and antitumor agent, thereby leading to completion of the present invention.
Namely, the present invention relates to an FGF inhibitor, angiogenesis inhibitor and antitumor agent containing complestatin or its derivative as an effective ingredient. In addition, the present invention also relates to a process for producing complestatin.